The knee joint has been described as the most complex joint of the human body. It contains four ligaments each limiting a specific directional movement and two fibrocartilagenous eccentric plates forming meniscus cartilage. The meniscus cartilage is made up of C-shaped fibrocartilage tissue located within the knee joint. The menisci, named the lateral meniscus and the medial meniscus are two tough pieces of fibrocartilage that rest between the femur and the tibia. Combined, these two menisci bear all of the weight of the body when an individual is standing. The cartilage allows the tibia and femur bones to slide over one another reducing friction between the bones and prevents damage from wear and tear. The meniscus cartilage also acts as a shock absorber preventing the bones smashing against each other with impact and functions as a stabilizer. However well designed it may be for ordinary movements, the meniscus is often no match for the uncertainties of a fall much less the rigors of modern everyday sports activities. A common injury of the knee is when the meniscus cartilage tears, or herniates with partial or complete extrusion of the meniscus. The tearing of the meniscus can result in swelling, inflammation and pain. The torn portion may also interfere with mechanical operation of the joint wherein the knee is locked.
At the present time, most meniscus tears are addressed using arthroscopic surgery techniques where surgeons repair or remove the herniated section. The partial removal of the meniscus—called a partial meniscectomy—using arthroscopic surgery causes less trauma to surrounding tissue than conventional surgical techniques. A partial meniscectomy is performed to remove only the herniated segment of the meniscus. This procedure has been reported to be successful over the short, and long term if the meniscus tear is relatively small. But for some large meniscus tears, a sufficient portion of the meniscus is removed such that problems will remain and long term prognosis is not optimal. Arthroscopic surgery can thus treat the wear and tear injuries related to a torn meniscus, which is the crescent-shaped cartilage that cushions the knee, as well as injuries to the surface of bone that makes joint movement painful. In lavage and debridement procedures, the surgeon identifies floating or displaced tissue pieces and either flushes them out with a solution applied with arthroscopy or smoothes the exposed surfaces to try to decrease pain.
Conventional meniscus repair surgery is conducted through the visualization offered by the lighted arthroscope that allows the surgeon to follow the surgery on a television monitor. Instruments which have a thickness of about 0.15 in (4 mm) are inserted in a triangular fashion around the knee. The arthroscope is inserted in a first incision, and the instruments used to cut and/or smooth and to otherwise manipulate the tissue are inserted through the other incisions. In this fashion, the surgeon has magnification, perspective, and the ability to make tiny adjustments to the tissue without open surgery. The triangular approach is considered highly effective and safe.
While arthroscopic surgery is advantageous and preferred over prior conventional surgical techniques, it still involves relatively large incisions into the knee for both the scope and the retractor that is used to incise the torn meniscus part from the larger structure and remove it from the surgical field. Consequently, the recovery from the surgery can take up to three to four months and may require the use of knee brace to either totally immobilize the knee or significantly restrict motion, such as a hinged knee brace. In addition, after surgery crutches are typically required along with the administration of narcotics to treat pain. The application of ice packs is recommended to reduce swelling. There is also some risk of infection. Steroid therapy may be also be employed in conjunction with or after the surgery for its anti-inflammatory reaction and its reduction of edema. In addition to the treatment of meniscus tears, arthroscopic surgery is performed to remove loose bodies within the synovial joint which may comprise displaced cartilage.
While arthroscopic surgery has been a conventional technique to treat meniscal tears and the removal of loose bodies, there exists a need for alternative and less invasive manner in which to provide effective treatment. Post operative narcotics, prolonged knee cooling with a special device and extended physical therapy is usually required.
Collagenase is an enzyme found in certain clostridia culture filtrates, and more especially culture filtrates of Clostridium histolyticum and Clostridium welchii; the former being the preferred source. As initially recovered, collagenase is impure and contains not only collagenase but a peptidase and trypsin-like proteinase. Its recovery in impure form is described by Mandl et al (Isolation and Characterization of Proteinase and Collagenase from Cl. histolyticum, J. Clin. Invest., 32, 1323 (1953)).
Currently, collagenase is used for debridement of third degree burns, in enzymatic separation of dermis and epidermis (Whole Mounts for the Study of Skin and its Appendages, J. Invest. Dermatol., 23, 437-453 (1954)). Collagenase also has been used in studies of different collagens by electron microscopy (Evaluation of Structural and Chemical Changes in Connective Tissue, Annals N.Y. Acad. Sci., 56, 674-683 (1952)). Collagenase may be purified as by chromatography so as to recover an enzyme consisting essentially of collagenase. Moreover, by the employment of conventional techniques to remove bacteria, the collagenase may be produced in sterile form. Collagenase has been purified by electrophoresis of enzyme preparations obtained by ammonium sulfate fractionation and has been the subject of biological investigation by Mandl et al., Clostridium Histolyticum Collagenase, Its Purification and Properties, Archives of Biochem. and Biophysics, 74, 465-475 (1958)) wherein its activity has been studied in regards to its ability to attack collagen and its degradation products and its inability to attack protein substrates such as casein or hemoglobin or the fibrous proteins, fibrin, keratin and elastin.
Thus, collagenase may be provided in dosage form appropriate for a single internal injection into a living mammal and, to this end, a sterile, purified solution of collagenase is introduced into a vial in sufficient quantity to provide the necessary volume for injection of a solution having a concentration of approximately 0.01 to 0.1 percent. The solution is then subjected to lyophilization to produce the collagenase in dry, sterile condition and the vial is sealed. At the time of use the aqueous medium used for injection is added directly to the vial. As aforesaid, the aqueous solvent may contain a small amount of buffered saline and calcium phosphate to provide the desired pH. The collagenase solution is ready for use as soon as it is prepared in this way.
Known procedures for the purification of the collagenase have been reported for many years. For example a procedure was described by Keller and Mandl, The Preparation of Purified Collagenase, Arch. of Biochem. and Biophys., 101, 81 1963. Prior to clinical use, a test portion of the collagenase that is produced should be tested to insure its essential freedom from proteolytic and elastolytic activity. The materials should also be tested for sterility and pyrogenicity.
Collagenase is also presently available in from of an ointments under the brand name Collagenase Santyl® (collagenase) and has an approved indication for debriding chronic dermal ulcers and severely burned areas. It is manufactured by Biospecifics Technologies Corp., 35 Wilbur Street Lynbrook, N.Y. 11563. The ointment is a sterile enzymatic debriding ointment which contains 250 collagenase units per gram of white petrolatum USP.
Collagenase has also been approved for the treatment of Dupuytren's contracture, a disease affecting the ligaments of the hand. The condition is characterized by an abnormal collagen buildup that forms a cord in the palm of the hand. The enzyme, collagenase clostridium histolyticum, is sold under the trademark Xiaflex by Auxilium Pharmaceuticals, Inc., 640 Lee Road, Chesterbrook, Pa. 19087. Xiaflex is supplied in single-use glass vials containing 0.9 mg of collagenase clostridium histolyticum as a sterile, lyophilized powder for reconstitution. Sterile diluent for reconstitution is provided in the package in a single-use glass vial containing 3 mL of 0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride.
Collagenase is also an investigational drug for the treatment of Peyronie's disease. In summary, the FDA has repeatedly found collagenase can be safely administered and its efficacy has been demonstrated in connection with a number of indications.
Collagenase has also been used experimentally for intervertebral discolysis. As reported by Sussman and Mann, Experimental Intervertebral Discolysis with Collagenase, Journal of Neurosurgery, Vol. XXXI, No. 6 pp. 628-635 (1969) collagenase was used in animal experimental studies. The paper reports that enzymatic dissolution of the nucleons pulposus and fibrocartilage of the intervertebral disc was consistently produced in dogs following local injection of collagenase. Id at 634. An initial clinical report discussing the results of a phase I trial involving human subjects was published in 1981, Sussman Bromley, Gomez, Injection of Collagenase in the Treatment of Herniated Lumbar Disc, JAMA Volume 245 No. 7 (Feb. 20, 1981) While denatured collagen is susceptible to many proteolytic enzymes, unaltered collagen is resistant to all common proteolytic enzymes. However, collagenase is reported to be a unique microbial enzyme as regards its capacity to attack native collagen under physiological conditions of pH and temperature. See also Sussman, Intervertebral Discolsysis with Collagenase, Journal of the National Medical Association, Vol. 60. No. 3 pp 184-187 (May 1968); See also U.S. Pat. No. 3,678,158 to Sussman, Treatment of Herniated Intervertebral Discs of Mammals.
Also relevant to the present invention are advancements in guided injection technology. While both CT and MRI have been used to guide injections, the associated radiation and considerable expense make these methods difficult for patients, doctors and staff. Further, CT and MRI techniques sometimes require the addition of iodine based contrast agents and cannot quickly capture the real-time motion of a needle. With the advent of ultrasonic needle guiding technology it is now possible to accurately inject medication in small joints. For example, in Botwin, Sharma, Salidba and Patel, Ultrasound-Guided Trigger Point Injections in the Cervicothoracic Musculature: A New and Unreported Technique, Pain Physician 2008; 11:885-889, ISSN 1533-3159, the authors report that ultrasound—guided trigger point injections using Sonosite MicroMaxx compact ultrasound system can achieve proper needle placement within the cervicothoracic musculature.
Guided injection systems are commercially available and marketed by, inter alia Fisher Biomedical, Inc. 740 Commerce Drive Suite 13, Venice Fla. 34292 under the SIUI CTS-880 line including the CTS-8800; UMI, 832 Jury Court, San Jose Calif. 95112 which markets the Sonosite M-Turbo Ultrasound that includes needle visualization software. Yet a further provider of an ultrasound needle guided injection systems is Diagnostic Instruments Inc., Mindray North America which sells a device under the Mindray MSK M7 brand. See also Astourian, Patrick, Ultrasound guided musculoskeletal injections, 2011.
Thus, ultrasound guided injection has been used for the administration of corticosteroids and other pain relief medication. See The Journal of Musculoskeletal Medicine. Vol. 27 No. 9 Arthritis Rheum 2010, 62:1862-18. See also The Journal of Musculoskeletal Medicine. Vol. 26 No. 11 J Rheumatol 2009, 36:1892-1902 (addressing intra-articular injections performed with ultrasound image guidance.)
It is therefore an object of this invention to provide a new and effective relatively non-invasive treatment method for meniscus tears. It is a further object to obtain analogous results to those obtained by current arthroscopic surgical techniques by the selective dissolution of the torn or floating meniscus comprised of fibrocartilage with a therapeutically effective amount of collagenase.